Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells.
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The lysosomal storage disorder galactosialidosis results from a primary deficiency of the protective protein/cathepsin A (PPCA), which in turn affects the activities of beta-galactosidase and neuraminidase. Mice homozygous for a null mutation at the PPCA locus present with signs of the disease shortly after birth and develop a phenotype closely resembling human patients with galactosialidosis. Most of their tissues show characteristic vacuolation of specific cells, attributable to lysosomal storage. Excessive excretion of sialyloligosaccharides in urine is diagnostic of the disease. Affected mice progressively deteriorate as a consequence of severe organ dysfunction, especially of the kidney. The deficient phenotype can be corrected by transplanting null mutants with bone marrow from a transgenic line overexpressing human PPCA in erythroid precursor cells. The transgenic bone marrow gives a more efficient and complete correction of the visceral organs than normal bone marrow. Our data demonstrate the usefulness of this animal model, very similar to the human disease, for experimenting therapeutic strategies aimed to deliver the functional protein or gene to affected organs. Furthermore, they suggest the feasibility of gene therapy for galactosialidosis and other disorders, using bone marrow cells engineered to overexpress and secrete the correcting lysosomal protein.
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Transplantation of Ppca−/− mice with transgenic bone marrow led to complete reversal of their systemic pathology, normalization of urinary oligosaccharides, and increased cathepsin A and Neu1 activities.
“Transplantation of Ppca−/− mice with the transgenic bone marrow led to complete reversal of their systemic pathology, normalization of urinary oligosaccharides and increased cathepsin A and Neu1 activities, although correction of the CNS pathology was only partial 53.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
The ‘Rescue of the galactosialidosis phenotype’ section reports normal urinary sialyloligosaccharide levels and complete reversal of the gross diseased phenotype after transplantation; the discussion describes complete reversal of lesions in visceral organs with transgenic marrow. However, the enzyme-activity increases in Table 3 were measured in deficient human fibroblasts exposed to transgenic-mouse serum or bone-marrow-conditioned medium, not in the transplanted mice. The histopathology section also notes residual storage in some autonomic ganglia, so ‘complete reversal’ is too broad for all systemic pathology. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTransgenic mice overexpressing human PPCA exclusively in erythroid precursors secreted it abundantly into the circulation.
“These transgenic mice overexpressed the human PPCA exclusively in their erythroid precursors and secreted it abundantly into the circulation.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
The BM transplantation section describes transgenic mice overexpressing human PPCA in the erythroid lineage, and the Rescue section reports that the secreted protein was detectable in plasma. The copy does not establish that overexpression occurred exclusively in erythroid precursors. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCorrection of CNS pathology in Ppca−/− mice transplanted with transgenic bone marrow was only partial.
“Transplantation of Ppca−/− mice with the transgenic bone marrow led to complete reversal of their systemic pathology, normalization of urinary oligosaccharides and increased cathepsin A and Neu1 activities, although correction of the CNS pathology was only partial 53.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
Ppca−/− mice have a clinical and pathological presentation that closely recapitulates early onset forms of GS, with no cathepsin A activity, severe secondary Neu1 deficiency, and β-Gal partially reduced only in some cell types.
“These mice have a clinical and pathological presentation that closely recapitulates the early onset forms of GS (Figure 2).”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
The secreted PPCA precursor was present in sufficient amount in the serum of transgenic mice to correct NEU1 and β-GAL activities when taken up by deficient patients' fibroblasts.
“Remarkably, this secreted precursor was present in sufficient amount in the serum of transgenic mice to correct NEU1 and β-GAL activities when taken up by deficient patients’ fibroblasts 53.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
Treated Ppca−/− mice lived longer than affected mice.
“Treated mice lived longer than affected mice.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [53]
The Phenotypic characterization section says untreated PPCA−/− mice die at about 12 months. The Rescue section reports reversal of disease signs after transplantation, including in a treated 10-month-old mouse, but gives no comparison of treated and untreated lifespans. Searches for survival, lifespan, and longevity found no such comparison in our copy. (LLM, conf=0.76)
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Cites
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Lu, S. C., Alvarez, L., Huang, Z.-Z., Chen, L., An, W., Corrales, F. J., Avila, M. A., Kanel, G., & Mato, J. M. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091016398 · Cited by 449 · see citing works
Gene therapy for lysosomal storage diseases
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Galactosialidosis: historic aspects and overview of investigated and emerging treatment options
Annunziata, I., & d’Azzo, A. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2016.1266933 · Cited by 50 · see citing works
Hermo, L., Korah, N., Gregory, M., Liu, L. Y., Cyr, D. G., D'Azzo, A., & Smith, C. E. (2007) · Journal of Andrology · doi:10.2164/jandrol.107.002980 · Cited by 27 · see citing works
- Authors
- Zhou, X. Y., Morreau, H., Rottier, R., Davis, D., Bonten, E., Gillemans, N., Wenger, D., Grosveld, F. G., Doherty, P., & Suzuki, K.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Wenger, D
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1995-11-01
- Volume
- 9
- Issue
- 21
- Pages
- 2623-2634
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W4300531881
- Cited by
- 131
- References
- 2
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- UNC Libraries
- Funders
- American Lebanese Syrian Associated Charities
- Erasmus Universiteit Rotterdam
- Erasmus+
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- galactosialidosis, lysosomal storage disease, PpcA, beta-galactosidase deficiency, neuraminidase deficiency, mouse model, bone marrow transplantation, erythroid precursors, transgenic overexpression, gene therapy, sialylated oligosaccharides, renal dysfunction, lysosomal storage
- MeSH terms
- Abnormalities, Multiple, Animals, beta-Galactosidase, Carboxypeptidases, Disease Models, Animal, Humans, Mice, Transgenic, Mutation, Neuraminidase, Phenotype, Erythroid Precursor Cells, Bone Marrow Transplantation, Lysosomal Storage Diseases, Cathepsin A, Mice
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